In a study recently published in Nature Cell Biology, there’s been a discovery that alters our understanding of how the body’s DNA repair process works and may lead to new chemotherapy treatments for cancer and other disorders. Because DNA is the repository of genetic information in each living cell, its integrity and stability are essential to life. DNA, however, is not inert. Rather, it is a chemical entity subject to abuse from the environment and any resulting damage, if not repaired, will lead to mutation and possibly disease.
The fact that DNA can be repaired after it has been damaged is one of the great mysteries of medical science, but pathways involved in the repair process vary during different stages of the cell life cycle. In one of the repair pathways known as base excision repair (BER), the damaged material is removed, and a combination of proteins and enzymes work together to create DNA to fill in and then seal the gaps. In addition to genetic insults caused by the environment, the very process of DNA replication during cell division is prone to error. The rate at which DNA polymerase adds incorrect nucleotides during DNA replication is a major factor in determining the spontaneous mutation rate in an organism.
Researchers discovered that BER has a built-in mechanism to increase its effectiveness, it just needs to be captured at a very precise point in the cell life cycle. In BER, an enzyme called polymerase beta (PolyB) fulfills two functions: It creates DNA, and it initiates a reaction to clean up the leftover chemical waste. Through five years of study, scientists learned that by capturing PolyB when it is naturally cross-linked with DNA, the enzyme will create new genetic material at a speed 17 times faster than when the two are not cross-linked. This suggests that the two functions of PolyB are interlocked, not independent, during BER.
Cancer cells replicate at high speed, and their DNA endures a lot of damage. When a doctor uses certain drugs to attack cancer cells’ DNA, the cancer cells must cope with additional DNA damage. If the cancer cells cannot rapidly fix DNA damage, they will die. Otherwise, the cancer cells survive, and drug resistance appears. This research examined naturally cross-linked PolyB and DNA, unlike previous research that mimicked the process. Prior to this study, researchers had identified the enzymes involved in BER but didn’t fully understand how they work together. This research improves the understanding of cellular genomic stability, drug efficacy, and resistance associated with chemotherapy, which, as previously stated, can lead to new chemotherapy treatments for cancer and other disorders.
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